视网膜色素上皮细胞通过p75NTR受体调控脉络膜新生血管生成的机制研究

项目名称： 视网膜色素上皮细胞通过p75NTR受体调控脉络膜新生血管生成的机制研究

项目编号： No.81200690

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 白玉婧

作者单位： 北京大学

项目金额： 23万元

中文摘要： 脉络膜新生血管(CNV)是年龄相关黄斑变性等致盲眼病的首要致病因素，目前唯一有效的治疗途径是抑制其生成及发展。视网膜色素上皮细胞(RPE)氧化损伤在CNV生成中具有重要作用。研究发现RPE氧化损伤能激活属于肿瘤坏死因子超家族的p75NTR受体，引起血管内皮细胞增殖，但其调控CNV生成的机制未明。本课题预实验发现RPE氧化损伤后p75NTR受体、血管内皮细胞生长因子、炎症因子表达均升高。为探索RPE中p75NTR受体与CNV生成的关系，本课题拟利用RPE细胞系、原代RPE及CNV动物模型，分析不同氧化损伤下RPE中p75NTR受体表达变化；并通过受体激动剂/抑制剂、基因过表达/基因敲减方法，研究RPE行为学功能，血管生成促进/抑制因子、基质金属蛋白酶/基质金属蛋白酶组织抑制剂、炎症因子及JNK信号通路表达变化；最后探索受体靶向性药物抑制CNV生成的疗效及可能机制，以期寻找CNV治疗新靶点。

中文关键词： p75NTR；视网膜新生血管；视网膜色素上皮细胞；年龄相关性黄斑变性；

英文摘要： Choroidal neovascularization (CNV) is the primary pathogenic cause of age-related macular degeneration (AMD). Until recently, the only effective treatment is to inhibit CNV generation and development. Retinal pigment epithelium (RPE) oxidative damage play a crucial role in CNV formation. Several studies have verified that under oxidative damage, the p75NTR receptor of RPE is activatied, which is one of the members of tumor necrosis factor superfamily, and promote vascular endothelial proliferation. However, the regulation mechanisms between p75NTR receptor and CNV generation is unclear. Our previous study validated that p75NTR receptor was elevated after oxidative stress in RPE, and induce the up-regulation of vascular endothelial growth factor and inflammatory cytokins. To explore the relation between p75NTR receptor in RPE and CNV generation, RPE cell lines, primary RPE and CNV animal model were used in this study. The dose-time dependent expression of p75NTR receptor was evaluated after RPE subject to oxidative damage; p75NTR receptor-target agonists/antagonists, gene overexpression/gene konck down method were used to study the behavior changes of RPE; the alteration of pro-/anti- angiogenesis factors, matrix metalloproteinase and tissue inhibitor of matrix metalloprotease, the inflammatory cytokines and JNK

英文关键词： p75NTR；retinal neovascularization；retinal pigment epithelium；age-related macular degeneration；